Chemistry • Year 12 • Module 8 • Lesson 12
Acid-Base Properties of Drug Molecules
Apply Henderson–Hasselbalch, read and interpret real ionisation data, and reason about drug behaviour in different physiological environments.
1. Interpret graph — % un-ionised aspirin vs pH
The graph below shows the percentage of aspirin present in the unionised (HA) form as a function of pH from 0 to 8. Aspirin pKa = 3.5. 9 marks
Calculated from Henderson–Hasselbalch: % un-ionised = 100 / (1 + 10pH−pKa). Aspirin pKa = 3.5. Adapted from TGA bioavailability reference data principles.
1.1 Describe the trend in % un-ionised aspirin as pH increases from 0 to 8. 2 marks
1.2 Using the graph, estimate the % un-ionised aspirin at stomach pH 1.5. State whether this means the drug is more likely to cross the stomach lining. 2 marks
1.3 At intestinal pH 6.5, approximately what percentage of aspirin is un-ionised? Explain the consequence of this for membrane crossing. 2 marks
1.4 Using the Henderson–Hasselbalch equation, verify that the [A−]/[HA] ratio at pH 1.5 is approximately 0.01. Show your working. 3 marks
2. Cause-and-effect chain — ibuprofen in the stomach
Ibuprofen is a weak acid with pKa = 4.91. A patient swallows an ibuprofen tablet. Trace the chain of events that determines how much ibuprofen is absorbed in the stomach. Fill in the empty effect boxes. 5 marks
Effect 1: The dominant form of ibuprofen is…
Effect 2: This form has… polarity and interacts… with the lipid membrane.
Effect 3: Membrane crossing is… compared with what would occur at a higher pH.
Overall: Ibuprofen absorption in the stomach is… because…
3. Interpret drug ionisation data
The table below summarises three drugs with different pKa values measured at two physiological pH values. All three are weak acids. 6 marks
| Drug | Type | pKa | [A−]/[HA] at stomach pH 1.5 | [A−]/[HA] at blood pH 7.4 |
|---|---|---|---|---|
| Aspirin | Weak acid | 3.5 | 0.010 | 7943 |
| Ibuprofen | Weak acid | 4.91 | 0.0004 | 3090 |
| Drug Z | Weak acid | 2.0 | 3.16 | 250 000 |
3.1 Identify which drug is the strongest acid and justify your answer using pKa. 2 marks
3.2 Compare aspirin and ibuprofen in terms of proportion un-ionised at stomach pH. Suggest which drug is more likely to be absorbed in the stomach and explain why. 2 marks
3.3 Drug Z has a very low pKa of 2.0 and therefore a high proportion ionised at stomach pH 1.5 (ratio 3.16). Explain the implication of this for gastric absorption of Drug Z. 2 marks
4. Predict and justify — antacid effect on aspirin absorption
A patient takes aspirin (pKa 3.5) together with an antacid. The antacid buffers the stomach pH from its usual value of approximately 1.5 up to approximately 4.5. 4 marks
Predict what will happen to the proportion of aspirin in the unionised form, and justify your prediction using the Henderson–Hasselbalch equation. Include a calculation of [A−]/[HA] at pH 4.5 in your answer.
Q1.1 — Graph trend
As pH increases from 0 to 8, the percentage of un-ionised aspirin decreases steeply from nearly 100% to nearly 0%. The curve has a sigmoidal (S-shaped) form, falling most steeply around pH 3.5 (the pKa), where exactly 50% is un-ionised.
Q1.2 — % un-ionised at pH 1.5
At stomach pH 1.5, the graph shows approximately 99% un-ionised aspirin. Because the dominant form is the uncharged HA, it is highly likely to cross the lipid membrane of the stomach lining (more membrane-permeable).
Q1.3 — % un-ionised at pH 6.5
At intestinal pH 6.5, the graph shows less than 1% un-ionised aspirin (<1%). Almost all aspirin is in the ionised A− form, which is far less able to cross lipid membranes; therefore gastric-style rapid membrane crossing does not occur in the intestine.
Q1.4 — Verification calculation
Using pH = pKa + log([A−]/[HA]):
1.5 = 3.5 + log([A−]/[HA])
log([A−]/[HA]) = 1.5 − 3.5 = −2.0
[A−]/[HA] = 10−2 = 0.01 ✓
This confirms the ionised form is present at a ratio of only 0.01 : 1, i.e. ≈99% is un-ionised.
Q2 — Cause-and-effect chain (model answers)
Effect 1: The dominant form is the unionised HA (un-ionised) form, because pH is well below pKa.
Effect 2: This form has low polarity and interacts weakly with the lipid membrane (compatible with the hydrophobic interior).
Effect 3: Membrane crossing is greater / facilitated compared with higher pH, because uncharged molecules diffuse through lipid bilayers more easily.
Overall: Ibuprofen absorption in the stomach is significant / favoured because stomach pH (1.5) is well below pKa (4.91), giving a high proportion of the unionised lipid-soluble form that can cross the gastric membrane.
Q3.1 — Strongest acid
Drug Z (pKa = 2.0) is the strongest acid. A lower pKa corresponds to a larger Ka and a greater degree of ionisation / stronger tendency to donate a proton.
Q3.2 — Aspirin vs ibuprofen at stomach pH
Aspirin ([A−]/[HA] = 0.010 at pH 1.5) has a larger proportion un-ionised than ibuprofen ([A−]/[HA] = 0.0004), meaning ibuprofen is even more un-ionised at stomach pH. Both drugs are predominantly un-ionised in the stomach, but ibuprofen (pKa 4.91) is proportionally even more un-ionised. Ibuprofen could therefore be absorbed as readily as or more readily than aspirin in the stomach, though the absolute difference in absorption may be small for both drugs at these very low ratios.
Q3.3 — Drug Z at stomach pH
Drug Z (pKa = 2.0) has a ratio of 3.16 at pH 1.5, meaning more drug is in the ionised form than the unionised form even in the acid stomach. This means a substantial fraction of Drug Z is charged in the stomach, reducing its ability to cross the lipid gastric membrane. Gastric absorption of Drug Z would therefore be lower than for aspirin or ibuprofen under the same conditions.
Q4 — Antacid effect
At pH 4.5, using pH = pKa + log([A−]/[HA]):
log([A−]/[HA]) = 4.5 − 3.5 = +1.0
[A−]/[HA] = 10+1 = 10
This means for every 1 un-ionised aspirin molecule there are 10 ionised molecules; i.e. the drug is now ~91% ionised.
Prediction: The antacid dramatically reduces the proportion of aspirin in the unionised form (from ~99% to ~9%), because the raised pH now exceeds the pKa. With less unionised aspirin available, the driving force for gastric membrane crossing is reduced, and aspirin absorption in the stomach will decrease. This is consistent with known TGA bioavailability concerns about antacid co-administration with aspirin.